Abstract
<jats:p>This systematic review and meta-analysis has several major aims, including evaluation of global and continent wise prevalence of diabetic peripheral neuropathies (DPNs), a detail assessment of DPN associated risk factors and most importantly to explore mechanistic basis of DPN by capturing its different pathophysiological hallmarks Diabetic peripheral neuropathy (DPN) imposes a substantial global burden, yet its mechanistic underpinnings and integrated risk architecture remain incompletely characterized. This systematic review and meta-analysis of 74 studies across 24 countries (83,560 participants) provides the most comprehensive quantitative synthesis of DPN prevalence, hallmark-based pathogenesis, and multi-covariate risk profiling to date. The global pooled DPN prevalence was 57.42% (95% CI: 48.56 to 66.05), with continent-specific gradients: Americas (74.52%), Europe (59.95%), and Asia (45.44%). Hallmark stratified subgroup analyses encompassing neuronal damage, metabolic dysregulation, neuroinflammation, and microvascular alteration identified microvascular alteration as the sole statistically significant mechanistic determinant (Q = 15.78, p = 0.0004), with prevalence escalating monotonically from 53% to 92% across increasing hallmark severity scores, constituting a compelling dose response relationship. Risk factor meta analysis of 27 covariates identified 12 significant determinants, including the novel meta analytic confirmation of peripheral vascular disease (OR: 3.70; highest effect size), male sex (OR: 1.52), and height (OR: 1.26) as independent DPN risk factors. Notably, HbA1c, BMI, and blood pressure were nonsignificant, challenging glycemia-centric paradigms. These findings collectively support a precision medicine framework grounded in hallmark stratified phenotyping and mechanism-targeted pharmacotherapy for DPN.</jats:p>